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1.
Cell ; 184(23): 5791-5806.e19, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34715025

RESUMO

Dynein-decorated doublet microtubules (DMTs) are critical components of the oscillatory molecular machine of cilia, the axoneme, and have luminal surfaces patterned periodically by microtubule inner proteins (MIPs). Here we present an atomic model of the 48-nm repeat of a mammalian DMT, derived from a cryoelectron microscopy (cryo-EM) map of the complex isolated from bovine respiratory cilia. The structure uncovers principles of doublet microtubule organization and features specific to vertebrate cilia, including previously unknown MIPs, a luminal bundle of tektin filaments, and a pentameric dynein-docking complex. We identify a mechanism for bridging 48- to 24-nm periodicity across the microtubule wall and show that loss of the proteins involved causes defective ciliary motility and laterality abnormalities in zebrafish and mice. Our structure identifies candidate genes for diagnosis of ciliopathies and provides a framework to understand their functions in driving ciliary motility.


Assuntos
Cílios/ultraestrutura , Microscopia Crioeletrônica , Mamíferos/metabolismo , Proteínas/metabolismo , Proteínas/ultraestrutura , Sequência de Aminoácidos , Animais , Bovinos , Cílios/metabolismo , Dineínas/metabolismo , Embrião de Mamíferos/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Proteínas dos Microtúbulos/química , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Modelos Moleculares , Mutação/genética , Traqueia/anatomia & histologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
2.
Biochem Soc Trans ; 49(3): 1221-1231, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34060618

RESUMO

Cilia are critical to numerous biological functions, both in development and everyday homeostatic processes. Diseases arising from genetic mutations that cause cilia dysfunction are termed ciliopathies. Several ubiquitously expressed splicing factors have been implicated in the condition Retinitis Pigmentosa (RP), a group of diseases characterised by the progressive degeneration of the retina. In many types of RP the disease affects the modified primary cilium of the photoreceptor cells and thus, these types of RP are considered ciliopathies. Here, we discuss sequence variants found within a number of these splicing factors, the resulting phenotypes, and the mechanisms underpinning disease pathology. Additionally, we discuss recent evidence investigating why RP patients with mutations in globally expressed splicing factors present with retina-specific phenotypes.


Assuntos
Cílios/genética , Ciliopatias/genética , Predisposição Genética para Doença/genética , Mutação , Fatores de Processamento de RNA/genética , Retinose Pigmentar/genética , Animais , Cílios/metabolismo , Cílios/patologia , Ciliopatias/metabolismo , Humanos , Precursores de RNA/genética , Precursores de RNA/metabolismo , Splicing de RNA , Fatores de Processamento de RNA/metabolismo , Retina/metabolismo , Retina/patologia , Retinose Pigmentar/metabolismo , Spliceossomos/genética , Spliceossomos/metabolismo
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